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Human Molecular Genetics Advance Access originally published online on December 16, 2008
Human Molecular Genetics 2009 18(5):942-955; doi:10.1093/hmg/ddn422
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© 2008 The Author(s).
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Mutant SOD1 impairs axonal transport of choline acetyltransferase and acetylcholine release by sequestering KAP3

Minako Tateno1, Shinsuke Kato2, Takashi Sakurai3,{dagger}, Nobuyuki Nukina3, Ryosuke Takahashi4 and Toshiyuki Araki1,*

1 Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan 2 Department of Neuropathology, Institute of Neurological Sciences, Tottori University Faculty of Medicine, 36-1 Nishi-cho, Yonago, Tottori 683-8504, Japan 3 Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan 4 Department of Neurology, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan

* To whom correspondence should be addressed. +81 423461716; Fax: +81 423461746; Email: taraki{at}ncnp.go.jp

Received September 11, 2008; Accepted December 9, 2008

Mutations in the superoxide dismutase 1 (sod1) gene cause familial amyotrophic lateral sclerosis (FALS), likely due to the toxic properties of misfolded mutant SOD1 protein. Here we demonstrated that, starting from the pre-onset stage of FALS, misfolded SOD1 species associates specifically with kinesin-associated protein 3 (KAP3) in the ventral white matter of SOD1G93A-transgenic mouse spinal cord. KAP3 is a kinesin-2 subunit responsible for binding to cargos including choline acetyltransferase (ChAT). Motor axons in SOD1G93A-Tg mice also showed a reduction in ChAT transport from the pre-onset stage. By employing a novel FALS modeling system using NG108-15 cells, we showed that microtubule-dependent release of acetylcholine was significantly impaired by misfolded SOD1 species. Furthermore, such impairment was able to be normalized by KAP3 overexpression. KAP3 was incorporated into SOD1 aggregates in human FALS cases as well. These results suggest that KAP3 sequestration by misfolded SOD1 species and the resultant inhibition of ChAT transport play a role in the dysfunction of ALS.

{dagger} Present address: Department of Pharmacology, Juntendo University School of Medicine. 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421 Japan.


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